The skin has historically been considered to function as a barrier against chemical or physical insults from the external environment. In addition to these barrier functions, the skin is now recognized to be an organ with important immunological and biochemical functions that can impact the health of the entire organism. Ultraviolet B radiation (UVB, 290-320nm) is responsible for the majority of cutaneous damage following both acute and long term exposure and is believed to be the single most important etiologic agent in human skin cancer. UVB carcinogenesis has recently been associated with an inflammatory response that includes the production and release of prostaglandins, which may be critical to the observed damaging effects of UVB on skin, which include the formation of oxidative DNA adducts. The underlying Hypothesis for the proposed studies is that there is a link between selective induction of one of the isoforms of the gene responsible for prostaglandin production, i.e. cyclooxygenase-2 (COX-2), and the resulting formation of oxidative DNA damage within the cutaneous microenvironment which ultimately results in the epigenetic and genetic alterations observed during UVB induced mutagenesis and carcinogenesis. Studies in the first specific aim will take advantage of the development of knock-out mice that do not contain either the constitutive isoform of the COG gene, COX-1 or mice which are COX-2 null. These studies will determine the critical nature of the presence of prostaglandins derived from these genes on the formation of DNA adducts, the induction of focal p53 clustering within the hyperplastic skin and to the kinetics of development and growth of UVB- induced papillomas and carcinomas. Studies in specific aim 2 will examine the ability of NSAIDS, specific inhibitors of the cyclooxygenase isoforms including, NS-398 and indomethacin, to prevent UV induced tumor growth. These studies offer a unique opportunity to gain insight into the role that COX-1 and COX-2 derived prostaglandins play in UV induced squamous cell carcinoma development and provide a potentially important pharmacological approach to abrogate or inhibit the deleterious effects of UVB exposure.